(1) Field of the Invention
The present invention relates to cyanoacrylate adhesives. In particular, the present invention relates to cyanoacrylate adhesives with an enhanced cure speed for medical use and that, once cured, exhibit improved permeability and mechanical properties such as, for example, wound closure strength, overlap shear strength, peel adhesive strength, and flexibility.
(2) Description of Related Art
Cyanoacrylate compositions have long been known in the art as excellent adhesives. The cyanoacrylate adhesives are liquid monomers that polymerize on contact with tissue surfaces in an exothermic reaction creating a strong yet flexible film. The polymer film is generally formed rapidly. Liquid cyanoacrylate compositions have found application in medicine for closing wounds and incisions, especially in cases where suturing does not provide satisfactory results because of cyanoacrylates unique ability to bond living tissue and their long-term bond strength. They have found wide applications as industrial and structural adhesives, consumer products for repair of household items and in the hobby sector for assembly and repair.
It is well known that cyanoacrylate adhesive compositions are very sensitive and careful handling is required to prepare their formulations. In order to extend the applications of cyanoacrylate adhesives, a variety of additives have been incorporated in their formulations including stabilizers, viscosity modifiers, thixotropic agents, plasticizers, biocompatible agents, and polymerization activators.
Cyanoacrylate polymerization is usually considered as the result of an anionic initiation with water being a sufficiently strong base. In spite of the relatively fast cure speed of cyanoacrylate adhesives, polymerization enhancers have to be incorporated for specific applications. First, the cure speed would be drastically dropped if cyanoacrylate adhesives were applied to acidic substrates such as wood and paper. In this case, the cyanoacrylate adhesives with a faster cure time would offer an option. In addition, a relatively large amount of cyanoacrylate applied in certain cases will result in the slower hardening throughout the adhesives.
In order to enhance the polymerization rate for such applications, a number of efforts have been made by applying accelerators through different methods. For example, a two component system has been used by packaging the cyanoacrylate adhesive and the accelerator separately. The cure speed of cyanoacrylate adhesives is improved. The disadvantage of this method is that the accurate measurement and mixing two components homogeneously are very difficult tasks to achieve since only a tiny amount of accelerators is generally required.
As an example, U.S. Pat. No. 5,928,611 to Leung discloses an applicator tip for dispensing a polymerizable material, in which a polymerization accelerator was included. The accelerator initiates polymerization when the polymerizable material is dispensed through the applicator tip. Suitable accelerators include detergent compositions; surfactants, amines, urea, phosphines, alcohols, inorganic bases and salts, sulfur compounds, polymeric cyclic ethers, crown ethers, calixarenes, cyclic and acyclic carbonates, organometallics, and radical. The polymerizable material may also contain an initiator which is inactive until activated by a catalyst in the applicator tip. Initiators activated by stimulation such as heat and/or light are also suitable if the tip and/or applicator is appropriately subjected to such stimulation.
U.S. Pat. Application No. 20050196431 to Narang et al. discloses an applicator tip for an applicator for applying a polymerizable monomeric adhesive composition that can include a bioactive material, a flavorant, a polymerization initiator, and/or a polymerization rate modifier. It has been discovered that the use of methanol, alone or as a component of a mixture of low boiling point solvents, to apply a polymerization accelerator to an applicator tip used to dispense monomer-containing adhesive compositions, provides an unexpectedly superior distribution profile of the material on, and within, the applicator tip. Applicator tips according to their invention can control the setting time of the polymerized or cross-linked adhesive, extend the shelf life of the monomer and control the flow properties of applied cyanoacrylate adhesives.
U.S. Pat. No. 4,460,759 to Narang discloses two-component adhesive compositions. One component contains the cyanoacrylate monomer and the second component contains a weakly acidic or weakly basic ionic accelerator consisting of a cation having a pKa of at least 10 and a nucleophilic anion.
Another approach to enhance the cure speed of cyanoacrylate adhesive is to apply the diluted solutions of the accelerators in low-boiling point solvents to the cyanoacrylate adhesives. The accelerator solutions can be added to the substrate in advance or applied when the cyanoacrylate adhesive is still liquid. Japanese Patent Application No. JP-A-03 207 778 discloses the use of solutions of aliphatic, alicyclic and, especially, tertiary aromatic amines as the activators for the curing of cyanoacrylate adhesives. Specific examples included N,N-dimethylbenzylamine, N-methylmorpholine and N,N-diethyltoluidine. Japanese Patent Application No. JP-A-62 022 877 suggested the use of solutions of lower fatty amines, aromatic amines, and dimethylamine for the same purpose.
British Patent Specification No. 1 230 560 described cyanoacrylate adhesive compositions containing certain substituted heterocyclic compounds as accelerators. The compositions may be presented in a two-part form, the first part comprising the cyanoacrylate adhesive and the second part comprising at least one of the substituted heterocyclic compounds, preferably dissolved in an organic solvent. The heterocyclic compound is invariably present in one part of a two-part composition because iminoethylene-substituted triazines and pyrimido-pyrimidines accelerate the polymerization so rapidly that they must be kept apart from the cyanoacrylate composition before use. An effective adhesive bond is obtained. However it is not concerned with an activator which is able to initiate polymerization throughout a layer of adhesive.
U.S. Pat. No. 3,260,637 to von Bramer discloses the use of a range of organic amines as accelerators for cyanoacrylate adhesives, particularly for use on metallic and non-metallic substrates. According to the invention, a catalyst solution comprising one or more organic amines was employed in a suitable solvent to moisten the surfaces to be bonded and to catalyze the adhesive action of cyanoacrylate adhesive composition.
U.S. Pat. No. 4,042,442 to Dombroski et al. discloses the addition of a polymerization initiator such as caffeine and theobromine to a cyanoacrylate adhesive composition. The caffeine or theobromine is added to the adhesive composition in different ways. Firstly, the caffeine or theobromine is dissolved in a volatile solvent, applied to the surfaces to be joined, the volatile solvent is allowed to evaporate, and then the cyanoacrylate adhesive composition is applied to the surfaces of the substrates to be joined. Secondly, the caffeine or theobromine can be mixed with the cyanoacrylate adhesive composition by stirring just prior to application of the adhesive to the substrates to be joined. Both of these methods are inconvenient for the user because two separate solutions or two separate applications are required.
U.S. Pat. No. 5,561,198 to Huver provided an activator for cyanoacrylate adhesives based on N,N-dialkyl aniline derivatives. The activators are characterized by a molecular weight of more than 200 and by at most 3 carbon atoms for both N,N-dialkyl substituents together. Their invention also provided methods of production and use of the activator and to the combination product of the activator and the cyanoacrylate adhesive. In their inventions, the activators were tested according to criteria including reactivity, cure rate on activated aluminum test strips, cure rate after activation, tensile shear strength on sand-blasted aluminum strips, transparency, and odor of the reactivity.
U.S. Pat. No. 6,547,917 to Hanns et al. revealed the accelerated curing of cyanoacrylate adhesives using organic compounds containing the structural element—N═C—S—S—C═N— in dilute solution as activators. Examples of such compounds include 6,6′-dithiodinicotinic acid, dibenzodiazyl disulfide, 2,2′-dipyridyl disulfide or bis(4-t-butyl-1-isopropyl-2-imidazolyl)disulfide. According to their invention, the activators are dissolved in readily volatile solvents, such as hydrocarbons, carboxylic acid esters, ketones, ethers or halogenated hydrocarbons. The activator solutions according to their invention are suitable for the accelerated curing of all conventional cyanoacrylate adhesives which contain as the fundamental constituent one or more cyanoacrylic acid esters, inhibitors of free-radical polymerization, inhibitors of anionic polymerization and, optionally, conventional auxiliary substances employed in such adhesive systems. As compared with the known accelerators, their method provided the following advantage: good accelerating action, but they nevertheless require a long waiting time between application of the activator and application of the adhesive.
U.S. Pat. No. 6,995,227 to Ryan et al. discloses an activator composition for the accelerated curing of cyanoacrylate adhesives, wherein the activator comprises a member selected from the group consisting of: aromatic heterocyclic compounds having at least one N hetero atom in the ring(s) such as pyridines, quinolines and pyrimidines and substituted on the ring(s) with at least one electron-withdrawing group which decreases the base strength of the substituted compound compared to the corresponding unsubstituted compound, mixtures of any of the foregoing with each other, and/or with N,N-dimethyl-p-toluidine, and mixtures of any of the foregoing and/or N,N-dimethyl-p-toluidine with an organic compound containing the structural element, such as dibenzothiazyl disulfide, 6,6′-dithiodinicotinic acid, 2,2′-dipyridyl disulfide, and bis(4-t-butyl-1-isopropyl-2-imidazolyl)disulfide. An activator composition may comprise a solution of one or more activators in a solvent mixture which comprises a volatile hydrocarbon and a cyclic ketone. Their invention reduced the problem of “halo” effect and provided activator solutions with different properties.
In order to improve the cure speed of cyanoacrylate adhesives, another important method is to incorporate accelerators directly to the adhesive formulations. DE-A40 09 621 proposed the use of certain cyclodextrine derivatives as an additive to improve the cure speed of cyanoacrylate adhesive, some of which are soluble in cyanoacrylates. GB-A-2 200 124 revealed the use of acyclic phenol-formaldehyde oligomers as an accelerating additive for cyanoacrylate adhesive formulations.
German patent DE-A-22 61 261 proposed accelerator substances containing the structural element —N═C—S—. According to their invention, cyanoacrylate adhesives containing such accelerators do in fact show that even relatively large amounts of adhesive harden relatively rapidly and reliably. However, that compound has a very high volatility, so that activator solutions based thereon are unsuitable for application beforehand since the active ingredient also evaporates off with the solvent.
U.S. Pat. No. 4,386,193 to Reich, et al. discloses a rapid-setting α-cyanoacrylate based adhesive composition having good storage stability and, in particular, to an adhesive composition having a very fast setting time on wood and other substrates with a porous/acid surface by using 3 or 4 arm polyol podand compounds as accelerators.
Japanese Patent Application No. 59-66471 discloses amine derivatives as a curing accelerator of cyanoacrylate adhesives. The amine compounds have a boiling point of between 50° C. and 250° C. Examples of suitable amines include propanolamine triethyl amine, diethyl amine, isopropyl amine, butyl amine, tributyl amine, N,N-dimethyl-o-toluidine, N,N-dimethyl aniline, N,N-diethyl aniline, N,N-dimethyl-p-toluidine, N,N-dimethyl-m-toluidine dimethyl benzyl amine, pyridine, picoline, vinyl pyridine, ethanolamine, and ethylene diamine.
U.S. Pat. No. 4,377,490 to Shiraishi et al., discloses mixtures of aromatic and aliphatic polyols and polyethers to improve initial strength of cyanoacrylate wood bonding products.
European Patent Specification No. 0 271 675 A2 discloses a primer for cyanoacrylate resin compositions for use in bonding non-polar or highly crystallized resins such as polyolefins, polyethyleneterephthalates, nylons, fluorine-containing resins, and soft PVC films. The primer comprises (i) an organic amine and (ii) a compound selected from the group consisting of benzene ring compounds having aldehyde group and nitrogen or oxygen atom-containing heterocyclic compounds having aldehyde group. The specification states that a cyanoacrylate adhesive exhibited a strong bonding strength at ambient temperature.
U.S. Pat. No. 4,718,966 to Stephen, et al. discloses cyanoacrylate adhesive compositions which employ calixarene compounds as accelerators give substantially reduced fixture and cure times on deactivating substrates such as wood, leather, ceramic, plastics and metals. The calixarene compounds are preferably employed at levels of about 0.1-1% by weight of the composition.
In U.S. Pat. No. 4,170,585 to Motegi et al., certain polyethylene glycols poly(ethyleneoxy) functional are disclosed to be additives for increasing the curing speed of cyanoacrylate compositions. Such compounds, however, have the reported disadvantage that they contain water and other substances difficult to remove which spontaneously initiate polymerization of the cyanoacrylate monomer.
Japanese Patent Application No. 8-310136 to Ohashi, et al. discloses 2-cyanoacrylate adhesive compositions containing a crown ether curing accelerator or a polyalkylene oxide curing accelerator. However, these compositions are not suitable for medical applications.
In general, cyanoacrylate combinations with accelerators have been obtainable by separately housing the cyanoacrylate and accelerator. The cyanoacrylate is then flowed past the accelerator housing to add the accelerator to the cyanoacrylate. This method is used for industrial applications, where large batches of the cyanoacrylate are needed. This method is not suitable for medical use, nor are the cyanoacrylate compositions prepared from this method amenable to being sterilized in preparation for medical use.
Based on the descriptions above, different design systems and a variety of chemicals have been applied to accelerate the curing speed of cyanoacrylate adhesives. However, most of the employed accelerators exhibited their own shortcomings at different extents. Some of them are more toxic, while others exhibit weak activation, less bond strength, high volatility and odor. In addition, irregular structure is formed in some cases, which destroys transparency of film. These disadvantages thus limit the application of cyanoacrylate adhesives in different fields, especially for medical use.
Moreover, in spite of the fact that many cyanoacrylate compositions have been disclosed for surgical wound dressing and management, none of the prior art cyanoacrylate-based surgical adhesives exhibit a desirable permeability or breathability. However, permeability, as measured by moisture vapor transmission rate (MVTR), is a desirable characteristic of a surgical adhesive because it prevents maceration of the skin due to trapped moisture, improve wound healing, and to enhance patient's comfort during wear of the bandage. Desirable permeability can provide the following benefits: (1) removing and preventing exudates from pooling while keeping the wound moist during the process of wound healing, (2) permitting appropriate oxygen ingress and carbon dioxide egress, and (3) minimizing the formation of trauma to surrounding or new tissue.
It has been reported that adhesives with high moisture vapor transmission rate improve wound care (Hansen et al. Adhesive Age 22-25, 2003). The prior art has emphasized the importance of permeability of wound dressing products on the wound healing process. For example, U.S. Pat. No. 4,649,909 to Thompson teaches a wound dressing made of polyurethane film. The moisture vapor transmission feature of the dressing film contributes to the improved wound healing. U.S. Pat. No. 6,495,229 to Carte et al. provides a method of speeding the healing of wounds using a rubber-based or acrylic pressure-sensitive adhesive bandage with high moisture vapor transmission rate. U.S. Pat. Appl. No. 20050182347 to Bishop et al. claims a multi-layered wound dressing comprising a layer having a high moisture vapor transmission rate (MVTR). The wound dressing possesses improved fluid handling capacity and high MVTR to reduce maceration of the surrounding skin and prevent wound desiccation.
Accordingly, there is a need in the art for a cyanoacrylate adhesive composition with a polymerization accelerator, which provides a desirable permeability or breathability for improved wound healing.